Implications of species difference for clinical investigation: studies on the renin-angiotensin system.
The justification for clinical investigation has its roots in the fact that physiological mechanisms and disease pathogenesis in animal models replicate mechanisms and pathogenesis in humans only in part. In the case of the renin-angiotensin system, there is species variation in the anatomic distribution of the renin-angiotensin system, in the active site of the renin enzyme, and in the structure of angiotensin and the AT(1) receptor. The conversion of angiotensin I (Ang I) to angiotensin II (Ang II) may prove to be the most important aspect of species variation. In plasma, all the conversion occurs through a single enzyme, angiotensin-converting enzyme (ACE), and species variation in structure and function have not been reported. Non-ACE-dependent pathways, which occur only at the tissue level, show unambiguous, striking species variation. Specifically, chymase, the most important enzyme responsible for non-ACE conversion of Ang I to Ang II, shows striking species variation. In humans and a number of species, including the hamster, quantitatively important chymase-independent Ang II formation from Ang I occurs in the heart, arteries, and kidney. In rats and rabbits, on the other hand, chymase differs, is not active in the conversion of Ang I to Ang II, and indeed is involved in Ang II degradation. Consequently, one would anticipate that blockade of the system at the ACE step would be equivalent to that at the Ang II receptor in the rat. This has been widely reported. In humans, on the other hand, one would anticipate that the AT(1) receptor blockers will be more effective than ACE inhibitors. Again, preliminary evidence favors this possibility. The implications for therapeutics are clear.